RESEARCH & RELATED - OTHER PROJECT INFORMATION - PROJECT SUMMARY/ABSTRACT CB2 cannabinoid receptor agonists show intriguing therapeutic promise in diverse preclinical models. However, the lack of detailed information about the signal transduction mechanisms underlying the observed in vivo efficacies has thwarted translational efforts aimed at developing CB2-based therapeutics. We have recently described striking functional selectivity (whereby different agonists activate distinct networks of signaling pathways) among different CB2 agonists. We hypothesize that the inability to move CB2 agonists forward from preclinical development to novel therapies is in part due to an insufficient appreciation of the functional selectivity of this class of drugs. We contend that understanding of the mechanism of CB2 agonist functional selectivity is a prerequisite for rationally designing CB2 agonists exhibiting functional selectivity for specific classical CB2 agonist signaling pathways. We will test the hypothesis that selective activation of a restricted set of signaling pathways will produce unique therapeutic benefits by evaluating the effects of novel, functionally selective CB2 agonists in four different preclinical models. This project works iteratively with Core B, and Projects 1 & 2 to systematically evaluate functional selectivity of the novel CB2 agonists synthesized in Project 1 (in vitro assays) and determine if CB2 agonist functional selectivity can be exploited to develop more efficacious CB2 agonists for the treatment of chronic pain, inflammation, and reward (in vivo assays). We will test our central hypothesis and accomplish these objectives by completing two specific aims: 1. To characterize the in vitro functional selectivity of rationally designed CB2 agonists from distinct chemical classes. The compounds showing the most distinct profiles of functional selectivity will then be advanced to the second specific aim. 2. To identify the optimal functional selectivity profile of CB2 agonists for suppressing neuropathic pain, inflammation, and reward in vivo. The most promising compounds identified in Aim 1 will be evaluated in Aim 2 for efficacy with acute and chronic (as appropriate) treatment. Completion of the first aim will map CB2 agonist chemotypes associated to specific patterns of functional selectivity. The second aim will identify signaling networks required to suppress neuropathic pain, inflammation, or reward in our preclinical models, which may or may not involve overlapping functional selectivity profiles. (This approach will also identify the signaling pathways that are not necessary (i.e. dispensable) for a particular behavioral outcome, which is important information to obtain and will be a helpful guide for future medicinal chemistry efforts.) Together, the knowledge gained from these aims will allow us and others to develop novel CB2 ligands with focused pharmacological efficacy and possibly reduced side-effects for treating indications where CB2 agonists are likely to prove beneficial.